Lung cancer represents one of the major public health problems worldwide. It has been estimated that between 1.3 and 2 million people died from lung cancer in the year 2000. The number of deaths caused by lung cancer exceeds those caused by the next three leading cancers together per year (breast, prostate and colorectal cancers). A decrease in mortality from lung cancer by improved diagnostic means would have an enormous impact on public health as well as reducing health care costs.
Ninety-nine percent of lung tumors are malignant, either primary or secondary. Non-Small Cell Lung Carcinoma (NSCLC) represents 80% of the bronchogenic carcinomas, which include Adenocarcinoma, SCC (Squamous Cell Carcinoma), LCC (Large Cell Carcinoma), and others. Small Cell Lung Cancer (SCLC), sometimes known as Oat Cell Carcinoma, comprises the rest of the cases. SCLC is the most aggressive type with a median survival of 2-4 months. Less common types include Sarcoma, Carcinosarcoma, Blastoma, Lymphoma, and Neuroendocrine tumors such as Carcinoids (both malignant and benign).
Since the lung parenchyma lacks nerve endings, tumors of the lung can become large before causing local symptoms such as coughing (75%), dyspnea (60%), pain (50%) and hemoptysis (30%). Fever, wheezing, stridor, hoarseness, SVC (Superior Vena Cava) syndrome, Horner syndrome, dysphagia, pleural effusion, and phrenic nerve paralysis may occur as well. Seventy percent of the patients have non-specific symptoms (such as anorexia, myalgia and weight loss), and a minority are asymptomatic. Some patients present with pneumonia due to bronchial obstruction, and some are diagnosed incidentally by a CXR (Chest X-Ray) assigned for another purpose. Since pulmonary lesions are commonly encountered in clinical practice, differentiation of benign from malignant tissue remains a challenge for the radiologist.
Early detection leads to better prognosis. For example, in stage I the survival rate is 60-70% and in stage Ia even higher. Unfortunately, only 15% of the cases are diagnosed at an early stage (I and II) when the tumor is well localized, so the overall survival rate has not risen recently. The one-year survival rate has increased from 32% in 1973 to 41% in 1994. However, the overall five-year survival rate is only 14%. Concerning lung metastases, the prognosis depends on the type of primary tumor and its biological behavior. For some carcinomas and sarcomas, the five-year survival after lung metastases excision is 25-45%.
The best chance of survival is expected when lung cancer presents incidentally on a CXR as a “coin lesion”, or single pulmonary nodule (“SPN”), which is single, peripheral and asymptomatic. The SPN is defined as an abnormal round/oval density of diameter<=3 cm, surrounded by lung parenchyma and lacking cavitations or pulmonary infiltrates. There could be eccentric flecks of calcifications, but not broad or concentric ring calcifications. Approximately 80% of the coin lesions are malignant in patients of age>50 years. Only when the lesion has been known to exist for at least two years without enlarging and with a “benign” calcification pattern, could histological diagnosis be delayed.
Only about half of lesions suspicious enough to undergo an open biopsy turn out to be malignant. This brings about needless morbidity and mortality, and the hospitalization costs of such a patient in the U.S. are about $25,000.
No fixed relationship exists between the size of a nodule and its biological behavior. It is possible that most patients already have metastases at the time of diagnosis, which the routine diagnostic tools do not always detect. This hypothesis is supported by clinical studies in which lymph nodes that appeared normal were found to contain metastases when evaluated by immunohistochemical staining or PCR (polymerase chain reaction).
There is general agreement among the various health organizations in the U.S., that the screening programs customary until recently (CXR and sputum cytology), have not contributed significantly to decrease the death rate. This is not true for the next three most common cancers: breast, prostate and colorectal, for which the death rate has decreased by 10-15% in the past 2 decades. It should also be noted, that in the Johns Hopkins Lung Project from the 70's, screening tests were negative in half of the patients that developed lung cancer, and became symptomatic before the next scheduled screening examination. A possible explanation was that some of the cases are so aggressive, that even strict follow-up and early detection will not increase survival. Actually, screening is intended mainly for NSCLC (75-80% of the cases), since SCLC is usually widely disseminated at presentation.
The progression and metastasis of lung cancer, as well as other cancers, depend on the capacity of the tumor cells to interact with their microenvironment and induce angiogenesis. This induction is mediated by a large number of angiogenic factors which collectively lead to capillary bud proliferation and sprout extension into the tumor, as well as migration of the tumor cells toward the vessels. Previous studies have shown that angiogenesis of lung cancer may begin early in the malignant process, as bronchial dysplasia and carcinoma in situ already have increased vascularity. In addition, the formation of a new capillary network in NSCLC correlated with tumor progression as well as an increased rate of metastases and poor prognosis. In an attempt to improve the prediction of prognosis, microvessels density (MVD) was also correlated with the tumor expression of different angiogenic factors such as the vascular endothelial growth factor (VEGF). However, recent studies of MVD in NSCLC did not find this parameter to be a predictor of survival. The contradictory results most likely present an inconsistency, as well as inter-observer variability of the MVD methodology.
In view of the need to improve lung cancer diagnosis and assessment of prognosis, as well as to test the efficacy of new antiangiogenic treatments targeted to lung cancer it is critical to develop non-invasive imaging methods that can quantitatively monitor temporal and spatial changes in tumor vasculature throughout the whole tumor.
Dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) provides an effective means of monitoring non-invasively and with high spatial resolution the microvascular properties of tumors. The increased permeability of tumor vasculature gives rise to increased leakage of tracers including MRI contrast agents, and enables characterization of enhancement patterns in the tissue. DCE-MRI has been applied to the evaluation of solitary pulmonary nodules (SPN) and, based on empiric quantifications of the contrast enhancement, a potential role for its use for non-invasive evaluation of SPN diagnosis and assessment of treatment was found. In previous clinical studies, Fujimoto et al demonstrated that MVD and VEGF-expression, in peripheral pulmonary carcinomas well correlated with contrast enhanced MRI empirical parameters. The empirical parameters included as maximal (peak) enhancement, curve slope and washout rate. Similarly, in contrast enhanced dynamic CT studies of primary lung carcinoma in patients it was found that the maximum attenuation values of time attenuation curves correlate with the number of small vessels and with endothelial cell markers and may predict VEGF-related tumor angiogenesis. The enhancement patterns can be further analyzed by mathematical models that relate the dynamic changes in the signal intensity to physiologic parameters such as the influx and efflux transcapillary transfer constants, which are also related to the surface area and permeability of the microvasculature.
MRI differentiates between solid and vascular structures, even without contrast material. Most importantly, MRI uses relatively harmless radio waves and there is no exposure to ionizing radiation as in CT. Due to longer acquisition time, patient movement is more detrimental. The potential role of dynamic contrast enhanced MRI-based evaluation of SPNs was first described by Hittmair et al. The maximum enhancement and the initial velocity of contrast uptake were assessed and correlated with pathohistological findings. Malignant neoplastic SPNs enhanced stronger and faster than benign neoplastic SPNs.
More recently, additional DCE-MRI studies of SPNs confirmed the early results. The parameters measured were peak enhancement and slope of enhancement and in some studies wash-out ratio and time to maximum were added as well. In Fujimoto's study, the DCE-MRI parameters correlated with tumor vascularity suggesting a potential use for this method to predict prognosis.
However, ways of determining two optimal MR data imaging times in contrast enhanced MR imaging in order to distinguish malignant from non-malignant tissue have still not been make known.